The genes of the HLA System, the major histocompatibility complex (MHC) of humans, control a variety of functions involved in the immune response, and influence susceptibility to over 40 diseases. Our understanding of the structure and function of MHC genes, their disease associations, and the evolutionary features of this multigene family has benefitted from recent advances in molecular biology, immunology, disease modelling and population genetics. Investigations by our group, and many others, have led to a deeper understanding of the molecular data and theoretical methods needed for the study of evolutionary and disease processes involving the genes of this highly variable, closely linked region. The specific aims of our research are to elucidate the evolutionary history of the HLA region, particularly the selective forces acting on HLA genes, and to delineate disease predisposing variants in the region. Our research methodology involves theoretical and empirical population genetic analysis of multilocus systems, for both allelic and DNA sequence data. A number of large HLA population data sets, including data on defined ethnic populations, will be available to us for analysis, as well as sequence data for HLA and MHC genes in other species. DNA sequence and frequency data will be available for HLA associated diseases. Our interests also extend to the study of non-HLA data. Our studies will include: HLA population single locus and multi-locus theory and data analysis, molecular typing of HLA class I and II genes in general and patient populations, single and multilocus analyses of MHC sequence data at the amino acid and nucleotide levels, mathematical modelling, simulation and data analysis of selection models for MHC regions, identification at the amino acid level of disease predisposing variants in the HLA region, and single and multilocus analyses of non-HLA population and sequence data. The results of our studies will contribute to inferences regarding the forces acting in natural populations, and how these contribute to the origin, maintenance and evolution of disease predisposing and protective alleles and other variants. Our studies apply generally to the mapping and characterization of the human genome and complex human genetic traits.